Method For the Production of Chemical and Pharmaceutical Products With Integrated Multicolumn Chromatography

ABSTRACT

The invention relates to a chromatographic process for substance separation in the context of the preparation of chemicals such as, for example, chiral pharmaceuticals, isomers or biomolecules on the small-scale and production scale, based on Simulated Moving Bed (SMB=countercurrent chromatography) technology.

The invention relates to a chromatographic process for substanceseparation in the context of the preparation of chemicals such as, forexample, chiral pharmaceuticals, isomers or biomolecules on the smallscale and production scale, based on Simulated Moving Bed(SMB=countercurrent chromatography) technology.

SMB is a process which allows continuous substance separations byimitating (simulating) the countercurrent between the adsorbent andmobile phase (liquid, gas or in the supercritical state).

U.S. Pat. No. 3,706,612 of A. J. de Rosset and R. W. Neuzil describes asimulated moving bed (countercurrent chromatography) unit on the pilotscale. Likewise, an operating problem is described there when such unitsare operated on the large scale and a circulating pump is utilized inorder to guarantee the circulation of the liquid in the process. Thisinvention (U.S. Pat. No. 3,706,612) describes the use of a valve at thestarting end of each adsorber bed in order to prevent an opposed flow.

U.S. Pat. No. 4,434,051 of M. W. Golem describes an apparatus whichallows countercurrent chromatography by utilizing a large number ofmultiway valves instead of a single rotary valve.

The separation of racemic mixtures on chiral adsorbents is described inan article in the Journal of Chromatography, 590 (1992), pp. 113-117; analternative arrangement of 8 adsorption chambers and 4 rotary valves isutilized there.

U.S. Pat. No. 3,268,605 describes a control system which controls theflow rate of three of the main streams by flow regulators and the fourthstream by means of a pressure regulator. A similar control concept forchiral substance systems is described in WO 92/16274 of Bayer AG. Thisreference uses a number of two-way valves in order to simulate thecountercurrent of the adsorbent.

In all these known techniques, however, the separating capacity isimpaired by the holdup volume of the circulation flow pump, which mustbe compensated by additional measures, such as, for example,asynchronous timing, alteration of the column lengths or flow adjustment[such as, for example, in EP 0688590 A1, Sepharex (Novasep),“Totvolumenkompensation der Kreislaufpumpe durch Reduktion des Volumens”(Dead volume compensation of the circulating pump by reduction of thevolume) (Lange); “asynchronous timing” as in EP 0688589 A1, Sepharex(Novasep); EP 0688588 A1 “Durchsatzanderung der Rezyklierpumpe”(Throughput alteration of the recycling pump)]. In DE 19833502 A1 ofNovasep, for this, the SMB base regulation by means of pressure isdescribed by simultaneous variation of at least two throughputs.

Consequently, the asynchronous timing in one zone was further developedto asynchronous timing in a number of or all zones (WO 00/25885 A).

For example, WO 93/04022 A of Daicel in which SMB is employed forresolution with subsequent re-racemization of the unwanted isomer, or WO91/13046 A of Daicel which likewise describes the use of SMB with achiral stationary phase for resolution afford examples of the use of SMBtechnology.

The prior art for the regulation of the internal and external mass flowsin simulated countercurrent chromatography is described, for example, inU.S. Pat. No. 4,499,115, U.S. Pat. No. 5,685,992, U.S. Pat. No.5,762,806, EP 960642 A1 and DE 19833502 A1.

Customarily, for the transport of the fluids 5 pumps are employed there,in each case one pump being located in the corresponding supply andoutlet lines—feed, eluent, extract and raffinate lines, and a furtherpump is arranged within a closed circuit. For the simulation of thesolid countercurrent, after a specific time interval, the timing periodτ, is retimed, i.e. by means of appropriate valve circuits the additionand removal sites are displaced around a column in the flow direction ofthe fluid phase. The circulating pump thus “migrates” through theindividual zones and transports different volume flows during a cycle.

FIG. 2 shows a customary SMB process. The fluid stream flows on SMBoperation in the circulation of a number of fixed bed columns filledwith adsorbent. The unit is subdivided into four functional zones by thecontinuous addition or removal of the feed, desorbent, extract andraffinate streams. Each one of these zones here takes on a specialseparation or workup function. Also shown is the recycle stream,transported by a recycle pump. Each functional zone, between thepositions of the external supply and discharge streams, are in each casesituated one to a number of chromatographic columns. The concentrationprofile established on suitable choice of the operating parameters inthe cyclically stationary state within the SMB unit of the maincomponents to be separated is shown schematically in the right sectionof FIG. 2 relative to the positions of the supply and discharge streamsat the point of time of the end of the cycle.

FIGS. 3 and 4 show schematically the apparatus construction of acustomary SMB process with the arrangement of individual valves in twosuccessive cycles. In the supply line of each column 2 individual valvesfor the switching of alternative feed or eluent stream and in the outletline of each column 3 individual valves for alternative raffinate,extract or recycling stream. On each further cycle, the valve circuitsare displaced by one position to the next column.

If the connecting lines between the columns are of different length andcontain a dead volume not to be neglected compared to the column volume,this fact must be taken into account, and a worsening of the separatingcapacity possibly associated therewith must be counteracted.Asynchronous switching of the valves (EP 688589 B1), specific adjustmentof the zone volumes (EP 688690 B2) or an adjustment of the output of thecirculating pump (EP 688588 B1) provide possible corrective measures.

For continuous operation as intended, the most exact possible adherenceto the internal and external mass flows is an indispensable requirement.For this, customarily three of the four supplied and discharged massflows (Q_(F), Q_(D), Q_(Ex) and Q_(Raf)) are constantly controlled,while the fourth part of the flow is readjusted by means of a specifiedsystem pressure such that this system pressure remains constant, bywhich the overall mass balance is adhered to.

This so far customary mode of operation of SMB chromatography unitstherefore has the following serious disadvantages:

-   -   The pressure regulation must on the one hand compensate all        malfunctions in the area of the mass flows as quickly and        exactly as possible, on the other hand it is itself in some        cases perceptibly disturbed by operation-related pressure        variations (e.g. also by the cyclical switching processes). In        particular in the case of high purity requirements and/or short        cycle times, this can lead to instabilities up to the loss of        the separating capacity.    -   The locking of the mass balance by means of pressure regulation        requires a permanently closed circulation. Short-term opening of        the circulation, e.g. for the discharge of impurities is thereby        not possible.    -   The internal circulating pump is confronted with continuously        changing mass flows, in addition this type of switching causes        variable dead volumes and thus inherent process malfunctions,        which must be compensated. As already mentioned, this frequently        proves to be difficult, in particular in the case of short cycle        times and demanding separation tasks.

In circuit operation as intended, in the SMB process generally 4internal (Q_(I), Q_(II), Q_(III) and Q_(IV)) and 4 external mass flows(Q_(F), Q_(D), Q_(Ex) and Q_(Raf)) exist, which are linked to oneanother by means of the following mass balances

Q _(I) =Q _(D) +Q _(IV)

Q _(II) =Q _(I) −Q _(Ex)

Q _(III) =Q _(II) +Q _(F)

Q _(IV) =Q _(III) −Q _(Raf)  (1)

For the setting of the working point, 3 external and one internal massflow and the timing period τ must be specified in such a way that theseparating task is achieved and thereby economical optimum operation isobtained with adherence to the specified product purities. The timingperiod τ here determines the “speed” of the apparent solidcountercurrent.

In the entire prior art, for the operation of the SMB, however,circulation pumps are fundamentally employed, which leads to theproblems already described due to the holdup volume of the pump.

It has now surprisingly been found that contrary to expectation nocirculation flow pump is necessary in order to maintain the fluidcirculation in an SMB.

The present invention therefore relates to an SMB process in whichinstead of the previously customary 5 pump concept a 4 pump concept isused by pumping the eluent stream with constant flow and extract,raffinate and feed stream. For the two outlet streams, alternativelycontrol valves instead of forced delivery pumps are also possible here.

FIG. 1 shows the principle of the SMB chromatography unit according tothe invention. The unit is only shown schematically here, for examplethe detailed line paths contained, the valve circuits and the otherinstrumentation are absent. In addition, for a better overview, theblocks shown in each case represent the functional zones and notindividual separating columns. The symbol FI represents a continuousflow measurement, FIC and LIC represent continuous flow or levelregulations including the measuring and control devices needed for this.Q, provided with different indices, in each case represents a mass flowwhich occurs in a certain position of the chromatography unit.

The circulation stream, as can be seen in FIG. 1, isinterrupted/separated by an intermediate container. In addition torobust mass flow regulation, this additionally allows a discharge offractions containing potential impurities in the running operation,which can be determined by suitable online analysis such as, forexample, UV, NIR, RI or US (in FIG. 1 marked as QIS). The pump arrangedin a fixed manner behind the intermediate container here conveys theeluent stream with constant flow directly to the first separating columnof the SMB chromatography unit, mainly independently of whether theeluent is discharged after flowing through the unit or fed back in aclosed circulation via the intermediate container.

In order that a circulation flow pump is saved and an eluent pump havingconstant flow is used, it is not necessary to compensate the separatingcapacity-disrupting holdup volume of the circulation flow pump byadditional measures, such as, for example, asynchronous timing,alteration of the column length or flow adjustment (see prior artabove). The further development of the asynchronous timing in one zoneto the asynchronous timing of a number of or all zones is thus alsosuperfluous, since the separating capacity in the process according tothe invention can also already be achieved directly by theholdup-optimized circuit of the chromatography unit according to theinvention.

Likewise, by the described discharge of contaminated eluent fractions inthe circulation flow, laborious stoppage or even startup and shutdown ofthe unit are avoided. In addition to the more robust control, thisfurthermore increases the economy of the process due to the describedinvention.

The more robust separating process of multicolumn chromatography incountercurrent operation according to the invention moreover allows amore efficient integration into the preparation process of chemicals andpharmaceuticals. Thus a reactor can be connected upstream and thestarting material connected directly as a feed to the multicolumnchromatography unit. Likewise, recovery of nontarget fractions afterfurther rearrangements or reactions, such as, for example,re-racemization by means of pH or temperature shift, are moreefficiently possible in the feed mixture or the reactor.

A further point is that both the downstream connected solvent workup andproduct workup by means of evaporation, drying and/or crystallizationsteps can be carried out more efficiently, since by means of thedescribed invention the throughput is higher, the product dilution lowerand the operating flows more constant; technically a working point canbe chosen which is nearer to the theoretical optimum.

In a particularly preferred embodiment, a novel modular valve system(MVS), which itself is also a subject of this invention, additionallyreplaces the known one-way or multiway fittings and is characterizedhere by its versatility. The process paths to be switched can berealized by incorporation of the valve heads in a single distributorbody. In addition, process parameters (such as, for example, pressure,temperature or concentrations) can also be determined by means ofappropriate adaptations. The MVS is distinguished by its compact mannerof construction, the modular expandability, cGMP-relevant features(avoidance of dead volumes, good cleanability) and high ease ofmaintenance. The valve seats can be replaced in the most simple mannerand adjusted to the needs. The compactness makes possible very shortcircuit times with very high circuit cycles. By means of thesesignificant improvements, the unit availability on the pilot andproduction scale can be markedly increased. Moreover, it is possibleusing this invention to operate units nearer to the theoretical optimumwhich increases the throughput/the productivity of the entire unit.

From WO 03/052308, a valve is already known which is of modularconstruction and can be actuated pneumatically. A characteristic of thisvalve is an extremely small closing stroke of the valve spindle. Onaccount of the construction of this valve, however, only amonodirectional flow of the valve is possible, whereby this valve isunusable for the use according to the invention.

In order to facilitate the simplification of the SMB process to theprocess according to the invention and to make possible an improved andthus preferred embodiment, it was necessary to develop a valve which hasextremely low closing times in the OPEN/CLOSED position, performs a verylarge number of switching cycles without showing wear phenomena,exhibits very low product-side dead spaces, has small structuraldimensions and can be flowed through with product from both sides, sothat in addition to the valve function in basic use operational cleaningprocesses by means of reversed flow directions and CIP (Cleaning inPlace) or SIP (Sterilization in Place) can also be accomplished simply.Moreover, high process requirements with respect to pressure andtemperature must not restrict the functionality of the valve. Inparticular in the case of a circuit of a number of valves in a verysmall space, it is absolutely necessary to produce compact valves havingfew components in a modular design, which make a very low holdup andthus sharp separating capacities possible in switching processes. Inspite of a small switching path, the ideal valve should have a positionindicator, by means of which the user can identify the actual valveposition at any time. The automatic or mechanical switching of the valveto a specified process-side safety position in the case of controlenergy outage should in the best case also still be made possible. Novalve known from the prior art can cope with these requirements in acompletely satisfactory manner.

Surprisingly, however, it is possible to build an MVS which particularlyfulfills the above-mentioned requirements. This MVS according to theinvention consists of a master board (10), on which at least one valveaccording to the invention is installed. The valve according to theinvention consists of a valve housing (20) and a control housing (30),the control housing having an interior pneumatic space, which is dividedinto a lower control space (33) and an upper control space (34) by apiston (31) having a seal (32). The lower control space is separatedfrom the valve housing by a closing plate (35) and additional seals(36). On the piston is located an extended valve spindle (37), whichruns through the valve housing up to the seal seat (11) in the area ofthe master board. The valve housing and the control housing are fixed toone another using a centering plate (21) with seals (22). The valvehousing is positioned relative to the master board using a secondfixing, the seal seat (11) using associated seals (12), such that achannel connection by means of the seal seat in the product space of thevalve housing is created by means of a supply channel (13) having alateral transverse channel (14) in the master board. From the productspace, in turn, a discharge channel (15) for product discharge isavailable, by which with the supply channel together a flow channel isformed. The valve spindle is bilaterally extended to the piston suchthat on the one hand the valve spindle reaches through the upper controlspace to outside the control housing and on the other hand the valvespindle is extended through the valve housing into the seal seat, thevalve spindle having a sealing contour to the valve seat and completelyclosing in the closed position the extended transverse channel andpreventing the product flow. The seal seat is positioned with its sealshalf in the master board and half in the valve housing, such that allvalve parts are centred and positioned during installation.

In addition, a characterizing feature of the MVS is that a number ofvalves are arranged in a space-saving manner, such that a common masterboard having a common central supply channel can admit at least twovalve seats having an identical number of transverse channels and formsparticularly low dead-space block valves which make possible thenecessary sharp substance separation in process chromatography by meansof appropriate control.

This type of valve according to the invention is characterized in afurther particular embodiment in that the pressurized control space andthe pressurized product space are separated by a pressure-less space andas a result leakage monitoring is made possible.

The valve according to the invention has a particular seal contourpairing between the lower, extended valve spindle and the seal seat,characterized in that different contour pairings and material pairingscombine in order to form concentric seal contours, which safely preventproduct flow in the closed position of the valve, a round to conicalcontour pairing preferably being used.

Further preferred contours for the valve spindle and seal seat areconcave and or convex designs of spherical and conical contours, butcombination with straight surfaces is also possible.

In one particular embodiment, the sealing valve spindle is designed suchthat the sealing ends of the valve spindle are hollowed out in order toemploy a complete sphere, to bond both parts, and to obtain an extremelysmooth surface contour for the sealing function. In a particularlypreferred embodiment of the valve spindle having a sphere, the sphereextends the valve spindle around the sphere radius and very particularlypreferably the sphere extends the spindle around the half radius.

Various embodiments of the valves on master boards offer particularadvantages for the acceptance of at least two of the valve setsaccording to the invention, the master board being designed in the formof a square or hexagonal rod and particularly preferably in spatialshape up to a dodecahedron, the number of valves situated on the masterboard being reduced by one to two based on all surfaces of the masterboard. By means of the common master board, it is possible to positiontwo, three, four and more valves in a very small space, one to two areashaving to remain free on the master board for the central supply anddischarge of the product.

The extension of the valve spindle by the control housing makes possiblethe external application of a position detector, which signals thecurrent valve position.

Likewise, a subject of this application is therefore also block valveswhich consist of a master board on which at least two valve housingseach having a control housing and in each case associated internalcomponents, and a position indicator is attached to each controlhousing.

The position indicator makes possible to the operator a visualindication of the actual valve position, which position indicator isbased on an electrical and or electronic and or mechanical signalgeneration, such that an inexpensive visual position indicator isproducible.

In a preferred embodiment of the valve according to the invention, thevalve seat is situated completely in the master board.

The closing stroke of the valve spindle is preferably less than 5 mm,particularly preferably less than 3 mm and very particularly preferablyless than 1 mm.

All metallic and nonmetallic materials can be used for the preparationof the valve.

In a further embodiment, the valve spindle contours seals the valve inthe seal seat and the diameter course of the concentric seal area of thetwo contours is greater than the hydraulic diameter of the transversechannel, preferably, the seal range is 1.1 to 1.3 times and particularlypreferably the seal area lies on a diameter in the seal seat of 1.4 to1.6 times the hydraulic diameter of the transverse channel.

The valves according to the invention are particularly suitable forguaranteeing a reciprocal sharply separating product flow in processchromatography units. Block valves of small construction with a centralmaster board are particularly suitable for use in process chromatographyunits.

In process chromatography units according to the invention whichessentially consist of a number of columns connected in series, thecolumns arbitrarily having to be capable of being cut off mutually or toone another, valves are continuously pressurized by means of the productsupply and the product discharge line, in addition the valves arealternatively switched at short time intervals in order, for example inthe case of different fractions (product specifications) to makepossible a rapid and sharp separation. Since the products are generallyexpensive, on account of the low closing stroke between the OPEN andCLOSED position the valve according to the invention increases theefficiency of the entire process chromatography unit. The high valvefunctionality of the valves, which is achieved in the form of a highleak tightness with, at the same time, a high number of switchingcycles, is particularly important. Use in batch chromatography units istherefore also possible.

FIGURES

FIG. A shows a four-valve block with master board

FIG. A′ shows the inventive valve with individual components

FIG. B shows, by way of example, a hexagonal master board or rod

FIG. C shows the preferred concentric seal area

FIG. D shows a particular design of the sealing valve spindle contour

In FIG. A, four inventive valves (1, 2, 3, 4), according to FIG. A′,installed on a common master board, are shown.

In FIG. A′, all individual valve parts are shown on a common masterboard (10). It can be seen in FIG. A′ that the master board (10) has acentral supply channel (11) for the product and from the supply channelfour transverse channels (14) branch off to the valves adapted to themaster board. At least two further valves can be installed on the masterboard, in which a further valve housing (20) and control housing (30)having appropriate fixing elements (e.g. screws) are detachablyconnected to the master board. The valve housing is centered on themaster board by means of the seal seat (11) and the centering of thecontrol housing is carried out using a centering plate (21), whichengages in the closing plate (35). In the control housing is a piston(31) having a firmly connected bilaterally extended valve spindle (37),in order to form an upper and lower control space (33, 34) in thecontrol housing. The extended valve spindle extends on the one side upto the seal seat and on the other side to outside the control housing,in order, if appropriate, to be able to admit a position detectoroutside the valve. The inner parts of the valve are provided withelastic seals, such that a product flowing through is specificallyconducted by the valve, cannot escape outward, product space and controlspace are separate from one another and leakage or failure of a seal isrecognized. In addition, the seals employed serve to seal individualvalve components in their planes. The seal (32) on the piston separatesthe upper and lower control space. The two seals (36) separate the lowercontrol space from the pressureless valve space, the inner seal sealingto the valve spindle and the outer seal sealing to the control housing.The centering plate (21) likewise has two seal (22) in one plane, suchthat one seals the product space to the valve spindle and the otherprevents a bypass flow. The centering plate has a transverse drilling(23), which is extended outwards through the transverse drilling of thevalve housing (24), such that a pressureless intermediate space isformed between the product space and control space. The transversedrillings signal a leakage or a failure of the product-side seals.

The flowing through of the valve with product takes place by means ofthe central supply channel, the transverse channel (14) and the sealseat, such that the end of the valve spindle contour is flowed aroundand the product can flow through the discharge channel (15) from thevalve. The product flowing through is prevented if, for example, anemployed pressure spring (38) in the upper control space presses thepiston with valve spindle into the contour of the seal seat. The valveopens if, for example, in the lower control space the attachedcompressed air builds up pressure and the compressive force generated isgreater than the spring force in the upper control space, such that thepiston is raised, the valve spindle separates from the seal seat, and aliquid or gaseous substance can pass.

In FIG. A, three further positions of the master board are occupied byvalves in order to form a four-block valve.

FIG. B shows the cross-section of a hexagonal rod or hexagonal masterboard (10), the central supply channel (13) and the transverse channels(14) being incorporated in the hexagonal master board, and a receivingdrilling of the seal seats being incorporated on each outer surface.FIG. B shows clearly that six valves with the valve housing (20) andcontrol housing (30) can be positioned in a narrow space and in the caseof a hexagonal rod even a multiple of six valves one after the other ishandleable in the narrowest space. It is not urgently necessary here,however, to equip each valve position.

In FIG. C, the special seal contours of the valve spindle (37) and ofthe seal seat (11) are shown. It can be seen that the preferred sealarea (X2−X1) is greater than the hydraulic cross-section of thetransverse channel. This has the advantage that with a high number ofswitching cycles at high differential pressures the sealing contours arenot deformed.

In FIG. D, a special form of the sealing valve spindle contour (37) isshown. Here, the production of a very smooth sealing surface is carriedout, by way of example, by the application of a sphere (37′). The sphereprojects here partially into the cross-section of the valve spindle anda part of the sphere is available elevated as a sealing contour.

An embodiment of the process according to the invention is likewisepreferred in which a certain mass flow control is employed, whichsurprisingly leads to a further performance increase and is likewise asubject of the present invention.

In the SMB unit according to the invention, the operating point isspecified by means of the external streams feed Q_(F), extract Q_(Ex)and raffinate Q_(Raf), and the internal eluent stream Q_(I) and timingperiod τ.

A mass flow control has now surprisingly been found (see FIG. 1), inwhich the mass flows Q_(F), Q_(Ex), Q_(Raf) and Q_(I) are continuouslymeasured and directly regulated by means of the speed of rotation of thecorresponding pumps (4-pump procedure). Alternatively, the adjustment ofthe product streams Q_(Ex) and Q_(Raf) by means of suitable regulatingvalves instead of discharge pumps is possible (2-pump procedure). Theadherence of the total mass balance, and thus the correct adjustment ofthe desorbent stream Q_(D) as the remaining external stream, is alsoachieved by the filling level regulation in the eluent receiver. Thisfilling level regulation compensates the deviations from the nominalmass balance inevitably caused by disturbances and/or measuring errorsand determines, together with the switching on of the nominal desorbentamount resulting from the balances,

Q _(D) ⁰ =Q _(Ex) +Q _(Raf) −Q _(F) +Q _(Dest)  (2)

the flow of freshly added desorbent (eluent):

Q _(D) =Q _(D) ⁰ +ΔQ _(D) ^(LIC).  (3)

This value is then adjusted by means of the flow regulation of thedesorbent amount and monitored by means of continuous flow measurement.

In a very particularly preferred embodiment, a continuous onlineanalysis measurement QIS is introduced into the recycle line after zoneIV (FIG. 1). In the case of contamination of the solvent stream fed back(e.g. breakthrough of product from zone IV), this triggers acorresponding valve circuit, such that the contaminated solvent streamis discharged and is not fed back into the eluent receiver.

The additional flow measurement in the recycle stream serves, in thecase of quality-related discharge of the recycle stream, for thedetermination of Q_(Dest), in operation as intended, by the utilizationof the redundancy achieved with the measurement of the flow Q_(Dest) inthe mass flow measurements and balances, a measurement data validation(data reconciliation) is performed for all mass flows and thus theaccuracy of the mass flow regulation is additionally increased.

The mass flow regulation according to the invention makes possible—inparticular by dispensing with a pressure regulation for the conclusionof the mass balance—a more accurate and more robust adjustment of themass flows for the confirmation of the separating capacity of the unit.

The very particularly preferred embodiment according to the invention ofa combination of the unit and regulation concept makes possible bothoperation with a closed and with an open circulation. In the case ofopen circulation, by means of the online analysis measurement in therecycle line, a possible impurity can be directly discharged. In theconventional circulation operation, discharge of impurities is onlypossible by means of the product streams and thus associated with a lossof yield.

The redundancy in the mass flow measurements provided according to theinvention and the measuring error balance for the flow measurementsbased thereon additionally increases the accuracy of the mass flowregulation and thus confirms the fulfillment of the separation task.

Using the unit and regulation concept according to the invention,variable dead volumes and the process disruptions associated therewithare avoided. Special countermeasures such as, for example, theasynchronous switching of the valves are thus no longer necessary.

The following examples are intended to illustrate the present inventionwithout, however, restricting it:

FIG. 5 shows the integration of the multicolumn chromatography processin an overall process for the preparation of chemical and pharmaceuticalsubstances as exemplified by racemic substances. There is thepossibility directly, without intermediate storage after the reaction,leading the reaction mixture continuously into the chromatography unit.Furthermore, the direct workup and the recycling of the solvent from theproduct streams extract and raffinate into the eluent receiver ispossible. The quality of the eluent must be measured and adjusted beforeuse again in the chromatography unit. For this, depending on the eluentcomposition required, a number of offline methods (such as, for example,GC and HPLC) and online methods (such as, for example, ultrasound,capacitative, NIR) are available. From a feed container, in a furthercontainer the feed mixture of solid or fluid consistency is introducedin the specified eluent composition. Extract and raffinate are suppliedfrom the chromatography unit to evaporators and the evaporated solventis recycled into the eluent container. Fresh solvent is metered in fromvarious eluent receiver containers, depending on the number of solventsinvolved in the eluent mixture, until the required eluent specificationis achieved in the eluent supply to the chromatography unit. Theconcentrated product after evaporating is stored in containers andgenerally crystallized, filtered and dried in the further productworkup. The byproduct—in the example case the “wrong” enantiomer—isusually re-racemized for economic reasons (often, for example, by pH ortemperature change) and after quality control added to the feed mixturederived from the original reaction stage.

1. A process for the separation of a substance mixture with the aid of acountercurrent chromatography process, in which a substance mixture tobe separated and the eluent are continuously supplied to a columncircuit consisting of more than one chromatography columns packed withan adsorbent and connected in series and in other positions of thecolumn circuit an extract stream comprising at least one separatedcomponent, and a raffinate stream comprising at least one othercomponent are continuously removed and in which a relative movementbetween a liquid, mobile phase consisting of the substance mixture andthe eluent and the adsorbent in solid phase is produced by sequentialopening of liquid addition and removal positions along the columns,characterized in that only one eluent supply pump and an eluentcompensation container, but no circulation pump is employed in thecirculation.
 2. The process as claimed in claim 1, characterized in thatat most 4 pumps are employed in the chromatography circulation.
 3. Theprocess as claimed in claim 1, characterized in that at least onedischarge pump, extract or raffinate discharge, is replaced by a controlvalve.
 4. The process as claimed in claim 1, characterized in that anautomatic discharge of contaminated eluent in the circulation is madepossible by means of an online detection and a control valve.
 5. Theprocess as claimed in claim 1, characterized in that the accuracy of themass flow control is increased by measurement of the recyclate streamand the redundancy thus achieved by means of a measured data balance. 6.The process as claimed in claim 1, characterized in that in the massflow regulation the adherence to the total mass balance is achieved bymeans of a filling level regulation in the eluent compensationcontainer.
 7. A modular valve technique (MVS), consisting of a masterboard, on which at least one valve, consisting of a valve housing and acontrol housing is installed, the control housing having an internalpneumatic space which is divided into a lower control space and an uppercontrol space by a piston having a seal and the lower control spacebeing separated from the valve housing by a closing plate and additionalseals, an extended valve spindle being present on the piston, which runsthrough the valve housing to the seal seat in the area of the masterboard, the valve housing and the control housing are fixed to oneanother using a centering plate with seals, the valve housing having asecond fixing, the seal seat with associated seals is positioned on themaster board such that by means of a supply channel having a lateraltransverse channel in the master board a channel connection is providedby the seal seat in the product space of the valve housing, where fromthe product space in turn a discharge channel for the product dischargeis present, by which with the supply channel together a flow channel isformed, furthermore, the valve spindle is bilaterally extended to thepiston such that on the one hand the valve spindle reaches through theupper control space to outside the control housing and on the other handthe valve spindle is extended through the valve housing into the sealseat, the valve spindle having a sealing contour to the valve seat andcompletely closing in the closed position the extended transversechannel and preventing the product flow.
 8. The MVS as claimed in claim6, characterized in that it is constructed on a master board in the formof a hexagonal rod.
 9. The process as claimed in claim 1, characterizedin that at least one valve system, as claimed in claim 6, is used.
 10. Aprocess for the preparation of a product, characterized in that theproduct mixture derived from the reaction is fed directly into a processas claimed in claim 1 and then worked up.